Costameric integrin and sarcoglycan protein levels are altered in a<i>Drosophila</i>model for Limb-girdle muscular dystrophy type 2H

Bawa, Simranjot; Gameros, Samantha; Baumann, Kenny; Brooks, David; Kollhoff, Joseph A; Żółkiewski, Michał; Cecconi, Andrea David Re; Panini, Nicolò; Russo, Massimo; Piccirillo, Rosanna; Johnson, David K.; Kashipathy, M.M.; Battaile, K.P.; Lovell, Scott; Bouyain, Samuel; Kawakami, Jessica; Geisbrecht, Erika R.

doi:10.1091/mbc.e20-07-0453

Cited by 14 publications

(16 citation statements)

References 81 publications

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“…Of note, glycogen can contribute to the formation of protein-polysaccharide complexes in muscle. For example, sarcoglycans, linking the actin cytoskeleton with the extracellular matrix to anchor the sarcolemma during muscle contraction, are altered by TRIM32 ablation in both the fruitfly and C2C12 cell models [31,32]. Taken together, these findings indicate that common pathways controlled by malin and TRIM32, even in a contrasting manner, may deserve further investigation to potentially identify novel therapeutic targets for both LD and LGMDR8.…”

Section: Regulation Of Glucose Metabolismmentioning

confidence: 87%

“…Regarding the C-terminal NHL repeats, no structural data is available for either protein, but the high sequence similarity between TRIM32 and malin would suggest that the NHL domain presents a similar three-dimensional structure. The crystal structure of the NHL domain of the TRIM32 Drosophila orthologue, thin, was recently solved and shown to fold in the typical beta-barrel shape (PDB 6D69; 6XG7) [31,32]. Using the Swiss-Model homology modeling software (https://swissmodel.…”

Section: Domain Compositionmentioning

confidence: 99%

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TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Kumarasinghe

García-Gimeno

et al. 2021

Cells

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Tripartite motif (TRIM) proteins are RING E3 ubiquitin ligases defined by a shared domain structure. Several of them are implicated in rare genetic diseases, and mutations in TRIM32 and TRIM-like malin are associated with Limb-Girdle Muscular Dystrophy R8 and Lafora disease, respectively. These two proteins are evolutionary related, share a common ancestor, and both display NHL repeats at their C-terminus. Here, we revmniew the function of these two related E3 ubiquitin ligases discussing their intrinsic and possible common pathophysiological pathways.

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Section: Regulation Of Glucose Metabolismmentioning

confidence: 87%

Section: Domain Compositionmentioning

confidence: 99%

TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Kumarasinghe

García-Gimeno

et al. 2021

Cells

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“…As with Brat and Lin41, the NHL domain of Mei-P26 and Thin/Abba also exhibit a highly positively charged patch on their top surface (Supplementary Fig. 1D) (3,31,55,56). Because it has been experimentally demonstrated that RNA binding in NHL domains occurs via this charged surface area, it was previously assumed that Mei-P26 NHL can also bind to RNA (3,6,31).…”

Section: Mei-p26 Nhl Binds To Single-stranded Rnamentioning

confidence: 59%

“…We compared the structure of Mei-P26 NHL to the NHL domains of Brat, Lin41 and Thin/Abba to gain further insights into their unique and commonly shared features (3,31,55).…”

Section: Mei-p26 Nhl Binds To Single-stranded Rnamentioning

confidence: 99%

Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26

Salerno-Kochan

Horn

Ghosh

et al. 2021

Preprint

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The TRIM-NHL protein Meiotic P26 (Mei-P26) acts as a regulator of cell fate in Drosophila. Its activity is critical for ovarian germline stem cell maintenance, differentiation of oocytes and spermatogenesis. Mei-P26 functions as a post-transcriptional regulator of gene expression, however, the molecular details of how its NHL domain selectively recognizes and regulates its mRNA targets have remained elusive. Here, we present the crystal structure of the Mei-P26 NHL domain at 1.6 Å resolution and identify key amino acids that confer substrate specificity and distinguish Mei-P26 from closely related TRIM-NHL proteins. Furthermore, we identify mRNA targets of Mei-P26 in cultured Drosophila cells and show that Mei-P26 can act as either a repressor or activator of gene expression on different RNA targets. Our work reveals the molecular basis of RNA recognition by Mei-P26 and the fundamental functional differences between otherwise very similar TRIM-NHL proteins.

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“…Drosophila body wall skeletal muscles have emerged as an important model system to determine the mechanisms of muscle growth and differentiation [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34]. Previously, we have found that FoxO overexpression in larval body wall skeletal muscles leads to myofiber atrophy and reduces developmental muscle growth [35], suggesting that the fruit fly Drosophila melanogaster can be used to identify evolutionary-conserved regulators of myofiber size [10,36,37].…”

Section: Introductionmentioning

confidence: 99%

A large-scale transgenic RNAi screen identifies transcription factors that modulate myofiber size in Drosophila

et al. 2021

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Myofiber atrophy occurs with aging and in many diseases but the underlying mechanisms are incompletely understood. Here, we have used >1,100 muscle-targeted RNAi interventions to comprehensively assess the function of 447 transcription factors in the developmental growth of body wall skeletal muscles in Drosophila. This screen identifies new regulators of myofiber atrophy and hypertrophy, including the transcription factor Deaf1. Deaf1 RNAi increases myofiber size whereas Deaf1 overexpression induces atrophy. Consistent with its annotation as a Gsk3 phosphorylation substrate, Deaf1 and Gsk3 induce largely overlapping transcriptional changes that are opposed by Deaf1 RNAi. The top category of Deaf1-regulated genes consists of glycolytic enzymes, which are suppressed by Deaf1 and Gsk3 but are upregulated by Deaf1 RNAi. Similar to Deaf1 and Gsk3 overexpression, RNAi for glycolytic enzymes reduces myofiber growth. Altogether, this study defines the repertoire of transcription factors that regulate developmental myofiber growth and the role of Gsk3/Deaf1/glycolysis in this process.

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Costameric integrin and sarcoglycan protein levels are altered in aDrosophilamodel for Limb-girdle muscular dystrophy type 2H

Abstract: Expression of human disease-causing LGMD2H alleles in Drosophila causes muscle degeneration and elevated levels of integrin and sarcoglycan costamere proteins, likely exacerbating disease progression.

Cited by 14 publications

References 81 publications

TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

TRIM32 and Malin in Neurological and Neuromuscular Rare Diseases

Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26

A large-scale transgenic RNAi screen identifies transcription factors that modulate myofiber size in Drosophila

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